1. Field of the Invention
The invention in a preferred embodiment relates to a simultaneous, one-stage resolution/racemization procedure for .alpha.-amino-.epsilon.-caprolactam. This invention relates also to a novel method for the racemization of optically active .alpha.-amino-.epsilon.-caprolactam at relatively low temperatures.
2. Brief Description of the Prior Art
Often one enantiomer of a compound having D- and L-forms is preferred over the other enantiomer of that compound. For example, lysine, an essential amino acid, exists in both D- and L-forms; however, only L-lysine possesses nutritional value. Although many synthetic methods for the production of lysine have been proposed, all non-biological methods have entailed preparation of either D,L-lysine or a D,L-racemic mixture of a lysine precursor such as D,L-lysine amide or D,L-amino-.epsilon.-caprolactam. If used in this racemic form, these precursors would lead to the production of D,L-lysine or salt thereof. Such a mixture might conceivably be used without separation of the non-nutritional D-isomer but such a procedure would result in considerable waste. It is therefore advantageous to separate or resolve the two enantiomers to recover the desired enantiomer and then to racemize the non-nutritional or useless D-enantiomer to form additional D,L-racemic mixture from which the desired L-enantiomer is again recovered, with the procedure being repeated as often as desired. In accordance with a procedure of this kind, essentially all the D-enantiomer is in course transformed into the desired L-form. Similarly for other compounds in which the D-, rather than the L-, enantiomer is desired, this procedure allows racemization of the L-enantiomer to yield additional D-enantiomer and subsequent recovery of the D-form.
Although methods are known to effect resolution and racemization of .alpha.-amino-.epsilon.-caprolactam as separate operations, no procedure is known which accomplishes both resolution and racemization in a single stage operation. An example illustrating resolution is the procedure disclosed in U.S. application Ser. No. 301,409, entitled "Resolution of .alpha.-aminocaprolactam", filed Oct. 27, 1972, now U.S. Pat. No. 3,824,231, wherein racemic mixture of D,L-.alpha.-aminocaprolactam are resolved in accordance with a method comprising:
a. forming a complex by admixing D,L-.alpha.-amino-.epsilon.-caprolactam at about 10.degree.-100.degree.C. in a solvent such as methanol, ethanol or isopropanol, or mixtures thereof, with metal ions, e.g. nickel in the plus 2 valence state; PA1 b. separating a solid phase rich in the D- or L-isomer by seeding the solution with crystals of an aminocaprolactam metal complex of the respective D- or L-isomer; PA1 c. recovering L-.alpha.-aminolactam from the precipitated L-isomer complex; PA1 d. racemizing the precipitated D-isomer complex and recycling to step (b). PA1 a. forming a supersaturated feed solution of an aminocaprolactam compound and maintaining said solution at a temperature of below 120.degree.C. and under conditions such that the racemization rate constant of aminocaprolactam is at least 0.001 min..sup.-.sup.1 ; PA1 b. contacting said solution with seed crystals of the desired isomer of said compound; and PA1 c. removing the grown crystals of said compound. PA1 L-acl.l-pyrrolidone carboxylic acid PA1 L-acl.d-n-carbamoyl valine PA1 L-acl.l-n-p-nitrobenzoyl glutamic acid PA1 L-acl.l-n-benzoyl glutamic acid PA1 L-acl.l-n-p-toluyl glutamic acid PA1 L-acl.l-n-p-chlorobenzoyl glutamic acid PA1 a. forming diasteromeric salts of ACL by reaction with one enantiomer form of an asymmetric acid in a suitable solvent, PA1 b. crystallizing preferentially the diasteromeric salt of the desired enantiomer of ACL and separating said preferred salt. Subsequently, steps are taken to recover the undesired enantiomer of .alpha.-aminocaprolactam, to racemize said enantiomer and to recycle same to step (a). In accordance with the invention, the crystallization of the diasteromeric salt of the desired aminolactam enantiomer can be effected under conditions such that racemization in solution of the undesired aminolactam enantiomer is relatively fast permitting a single stage resolution/racemization.
Racemization of optically active .alpha.-amino-.epsilon.-caprolactam in the presence of Ni.sup.+.sup.+ and other transition metal ions is disclosed also in U.S. Pat. No. 3,692,775.
It is also known that the racemization of optically-active aminolactams and amides of amino acids can be carried out in the presence of sodium by distillation in the absence of a solvent under vacuum at elevated temperatures, e.g. 180.degree. to 190.degree.C. This process has the disadvantage that high temperatures must be employed and only about 70% recovery is obtainable; these conditions add substantially to the expense of such process. Another process wherein racemization of aminolactams occurs by sodium hydroxide treatment in the presence of organic solvents, such as toluene and other hydrocarbons, is disclosed in U.S. Pat. No. 3,105,067. This process has the disadvantage that the comparatively high boiling point of the solvent makes it difficult to obtain a solvent-free product and adds to the heat requirements needed to recover the solvent for recycle. These conditions, moreover, add substantially to the capital investment and the operating costs of such process.
Because crystallization of the desired enantiomer occurs only from a supersaturated solution of the enantiomer to be recovered, only a small fraction of the desired enantiomer can be recovered in one crystallization stage before the supersaturation is depleted. The extent of crystallization may be increased by simultaneously removing solvent, e.g. by evaporation. In that case, however, the concentration of the undesired enantiomer would increase and eventually it would also crystallize out, thus disrupting the resolution. It is, therefore, necessary to keep the extent of crystallization, i.e. resolution, at a relatively low level. The remaining solution consists of the rest of the desired enantiomer and the undesired enantiomer. Since previously known racemization techniques require the application of elevated temperatures which produces significant losses of the desired enantiomer, it has heretofore been undesirable, therefore, to racemize the entire mother liquor remaining after one crystallization step because of the irretrievable thermal loss of the desired enantiomer in the racemization process. For this reason a method has been employed which entails passing the D,L-.alpha.-aminocaprolactam/metal complex solution over alternate beds of D- and L-seed crystals. After contacting a solution of either isomer with a D- or L-seed bed and depositing part of the D- or L-isomer, the liquor is re-enriched by dissolving additional D,L-.alpha.-aminocaprolactam metal complex, e.g. by heating at a higher temperature, and/or part of the solvent evaporated off to concentrate the solution and thereby facilitate further precipitation of the other isomer; the solution is then passed to a seed bed of the other isomer, which isomer is preferentially precipitated. After passing over the alternate isomer seed beds with concentration or enrichment after each precipitation, the solution will contain approximately equivalent concentrations of both isomers. New D,L-mixture is continuously added to the recycling process stream, with D- and L-isomer crystals being separately deposited from the solution onto the beds. After recovery, the undesired D-crystals are then dissolved, racemized and recycled while the desired L-crystals are separated from the metal complex and further treated.
If a method could be provided which effects racemization of .alpha.-amino-.epsilon.-caprolactam at relatively low temperatures and with substantially no loss of .alpha.-amino-.epsilon.-caprolactam, it would be advantageous because it would permit racemization of the entire mother liquor remaining after recovery of the desired .alpha.-amino-.epsilon.-caprolactam enantiomer; thus greatly simplifying the resolution/racemization process.
A still greater simplification would result, however, if it could be demonstrated that racemization of the undesired .alpha.-amino-.epsilon.-caprolactam enantiomer could take place simultaneously with the resolution of the desired enantiomer. In this case, the resolution/racemization process would take place in a single stage, thus eliminating the need for a separate racemization reactor. Moreover, since the undesired enantiomer would be continuously transformed to the desired enantiomer by means of racemization, it would become possible to effect high recovery of the desired enantiomer in a single pass without danger of crystallizing at the same time as the undesired enantiomer.
There is thus a need for a method in which resolution of racemic compounds may be effected simultaneously with racemization of the undesired optical isomer so as to effect a single stage operation.
There is also a need for a racemization method which may be effected at relatively low temperatures thereby allowing racemization of a mixture containing both the desired and undesired enantiomers without suffering a loss of the desired enantiomer.